Noxazinol is described in U.S. Pat. No. 4,420,480 by Jones along with a process for its preparation. This prior art process requires several steps but most importantly results in a racemic product which must be resolved to obtain the desired enantiomers which results in the loss of at least 50% of synthetic product.
Similarly with Dykstra et al., Eur. J. Med., Chim. Ther. 247-250 (1985); and Jones et al, J. Med. Chem.. 27. 1607-1613 (1984), the final product or intermediate must be resolved resulting in loss of synthetic material.
Chemistry similar to some of the steps in the novel process of this invention have been described in the literature. For example McClure et al., J. Org. Chem. 46, 2431-2433 (1981) describes a Friedel-Crafts ring closure similar to the step 4.fwdarw.5 in Reaction Scheme I but involves formation of a 5-membered ring fused to an unsubstituted benzo group. Also McClure et al J. Org. Chem.. 48, 2675-2679 (1983) describes the same ring closure to form a 6-membered ring fused to an unsubstituted benzo group. It further describes a failure to ring close to a 5-membered fused ring wherein the benzo group carried a methoxy meta to the point of closure. This suggests the claimed step 4.fwdarw.5 would not work.
Now with the present invention there is provided a novel process which starts with a simple chiral synthon, D-aspartic acid, from which noxazinol is elaborated in a sequence of steps each of which proceeds in high yield and retention of enantiomeric purity.